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Author: The Wistar Institute

Highlighting Vaccine Research at The Wistar Institute Through the Penn-CHOP-Wistar Vaccine Symposium

From HIV to COVID-19, Wistar scientists are at the forefront of vaccine development. Read our recap of the recent Vaccine Symposium and the impactful research in progress at the Institute.

This past Monday, The Wistar Institute, University of Pennsylvania Perelman School of Medicine, and Children’s Hospital of Philadelphia held the Penn-CHOP-Wistar Vaccine Symposium. Hosted both in-person at the Smilow Center for Translational Research and online, the all-day event covered the history of vaccines and current vaccine research from the three sponsoring institutions.

Keynote speaker and Wistar professor emeritus Stanley Plotkin, M.D., is a prominent researcher who is known for the development of the rubella vaccine while he was a virologist at The Wistar Institute. Furthermore, his years of work helping in vaccine efforts for rabies, rotavirus, and cytomegalovirus have stimulated much innovation in the biomedical research community.
After giving a brief history of vaccines, Plotkin proclaimed “Vaccinology has taken off. … We are now in a golden age of vaccinology.”

The Symposium’s research presentations opened with Wistar’s Daniel Kulp, Ph.D., Associate Professor in the Vaccine & Immunotherapy Center, and his work on a novel COVID-19 nanoparticle vaccine. Amelia Escolano, Ph.D., Assistant Professor in the Vaccine & Immunotherapy Center, also spoke about her efforts investigating immunization strategies for HIV. Wistar’s Vaccine & Immunotherapy Center Director David B. Weiner, Ph.D., gave a summary of his research into the genetic delivery of vaccines, calling the innovation of vaccinology in Pennsylvania among these institutions “extraordinary”.

The current global pandemic has reinforced the need for scientific solutions and a deeper understanding of human diseases. It is the studies and ideas from research centers like The Wistar Institute and its colleagues that propel forward biomedicine. As keynote speaker Plotkin stated, “Pandemics have occurred throughout the history of humankind and will continue to do so in the future. Infectious diseases of humans will continue to happen. Therefore, we must act against them.”

Distinguished Lectures in Cancer Research Series: The Eukaryotic RNA-protein Interaction Code: Binding, Interfaces, and Evolution

Scientific Seminar
Tuesday, Apr. 26, 2022

The Distinguished Lectures in Cancer Research series is the flagship seminar series of the Ellen and Ronald Caplan Cancer Center and features national and international leaders in basic and translational cancer research. Recent speakers (2020-2021) included Paul Mischel, Mark Yarchoan, Maria Blasco, Job Dekker, Nicholas Proudfoot, Moshe Oren, and Judith Varner, among others.

This seminar series is hosted in either Caplan or Grossman Auditorium on Tuesdays from 12:00 – 1:00pm and is targeted to graduate and undergraduate students, staff, faculty, and anyone interested in cancer research.

If interested in attending or if you have any questions, please email Deborah Johnson at djohnson@wistar.org.

Speaker

Quaid Morris, Ph.D.
Memorial Sloan Kettering Cancer Center
The Eukaryotic RNA-protein Interaction Code: Binding, Interfaces, and Evolution
Faculty Host: Bin Tian, Ph.D.

The Wistar Institute
Caplan Auditorium
3601 Spruce Street
Philadelphia, PA, 19104

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Distinguished Lectures in Cancer Research Series: Understanding the Role of Metabolism in Cancer

Scientific Seminar
Tuesday, May 24, 2022

The Distinguished Lectures in Cancer Research series is the flagship seminar series of the Ellen and Ronald Caplan Cancer Center and features national and international leaders in basic and translational cancer research. Recent speakers (2020-2021) included Paul Mischel, Mark Yarchoan, Maria Blasco, Job Dekker, Nicholas Proudfoot, Moshe Oren, and Judith Varner, among others.

This seminar series is hosted in either Caplan or Grossman Auditorium on Tuesdays from 12:00 – 1:00pm and is targeted to graduate and undergraduate students, staff, faculty, and anyone interested in cancer research.

If interested in attending or if you have any questions, please email Deborah Johnson at djohnson@wistar.org.

Speaker

Matthew G. Vander Heiden, M.D., Ph.D.
Koch Institute for Integrative Cancer Research at MIT
Understanding the Role of Metabolism in Cancer
Faculty Host: Rugang Zhang, Ph.D.

The Wistar Institute
Caplan Auditorium
3601 Spruce Street
Philadelphia, PA, 19104

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The Wistar Institute Cancer Center to be Renamed with $10 Million Gift from Caplan Family to Advance Cancer Research

PHILADELPHIA — (March 8, 2022) — The Wistar Institute announces that Ronald Caplan, founder and president of PMC Property Group, Inc., and his wife Ellen have donated $10 million to Wistar’s prestigious National Cancer Institute (NCI)-designated Cancer Center, which will be renamed the Ellen and Ronald Caplan Cancer Center of The Wistar Institute.

The gift to Wistar, the nation’s first independent biomedical research organization, will foster Wistar’s world-leading scientists in their high-impact discoveries toward promising cancer therapies. The investment will also further Philadelphia’s growing recognition as a life science innovation hub.

“Despite recent progress, cancer is still a feared disease carrying enormous morbidity and mortality for patients and their families. Ellen and Ron’s vision is to change that: their generous gift will dramatically accelerate the pace of innovation and discovery at our renowned cancer research center,” said Dario C. Altieri, M.D., president and CEO of The Wistar Institute, director of the Ellen and Ronald Caplan Cancer Center, and the Robert and Penny Fox Distinguished Professor. “We are enormously grateful to the Caplans for their unwavering support and transformative leadership as we prevail in our mission to discover new ways to detect, treat, and defeat cancer.”

The Caplans have deep ties to Wistar. Ronald has been a member of the Institute’s Board of Trustees since 2009; in 2014 he and Ellen donated the 200-seat high-tech Sarah and Matthew Caplan Auditorium in the Robert and Penny Fox Tower – named for their children in the hope that cancer’s cure would be found in their lifetime.

Wistar’s Cancer Center became the nation’s first NCI-designated cancer center for basic research in 1972 and is among only seven such centers in the U.S. to continuously hold this distinction for a half century. The Cancer Center has a history of impactful advances in cancer genetics, cancer biology, tumor immunology, and virology, including the identification of genes associated with different tumor types, the development of monoclonal antibodies used to study pathways and proteins involved in tumor development, and contributions to improved cancer treatments and diagnostic tests.

Achieving NCI’s highest ranking of “exceptional” in the last two consecutive Cancer Center Support Grant renewal applications, the Cancer Center now becomes one of only a few named biomedical research cancer centers in the country.

The newly envisioned Ellen and Ronald Caplan Cancer Center will help transform the prevention and treatment of cancer by advancing fundamental and translational research into next-generation therapeutics. This will involve expansive recruitment of new leaders in cancer research focusing on key areas of treatment resistance, metabolic and cellular reprogramming, cancer systems biology and personalized anticancer strategies.

“Ellen and I are honored to invest in the source of scientific discovery – the scientists whose life-changing breakthroughs will continue to bring us one step closer to a future without cancer,” said Ronald Caplan.

“Wistar scientists are some of the most dedicated, brilliant people we have ever met. Thanks to their incredible work, Wistar is the one place where every time Ron and I leave, we feel inspired,” said Ellen Caplan.

Learn more about the Ellen and Ronald Caplan Cancer Center below.

Note: Photos are available on request.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

Wistar’s Education & Training Team Visits Vaux High School to Connect on Life Science Careers

Wistar’s Drs. Kristy Shuda McGuire, dean of biomedical studies, and David Zuzga, associate dean of biomedical studies, spent an evening with students at Vaux Big Picture High School in north central Philadelphia to discuss all the STEM job opportunities available and for the taking here in the region.

Dr. Shuda McGuire spoke to Wistar’s education programs—available to high school students and upwards to postdoctoral fellows. She discussed how collaboration with academia and industry have made Wistar’s Biomedical Technician Training Program and Biomedical Research Technician Apprenticeship effective and successful vehicles to give students the needed skillset to enter coveted biomedical and biotechnical jobs. Then she imparted a little history on where and how Wistar fits into the dynamic regional life science hub we know today—from its beginnings as the first biomedical research institute in the nation, to how it has become a connector and engine for education in the burgeoning Philly biotechnology space.

Dr. Zuzga laid the groundwork on all the amazing science taking place in Philadelphia—from CAR T cell-trained assassins that became the first FDA-approved cell therapy to cure cancer in people who had no other options, to a new gene therapy company that created the first medicine to cure blindness. Dr. Zuzga drove home the point that the industry is booming in Philadelphia and students should set out and stake their claim in it. He emphasized that 10-years ago there were one or two cell and gene therapy companies and now there are more than 40 and the number is growing.

Basir Fulmore, a graduate of Cheyney University who is working in science, wrapped up the event and spoke to the students about his career trajectory. He talked about where he came from, the life lessons he learned in the process of attaining his science education and the true affinity he holds for science. He is a math and science teacher now but shared many stories of working in a Cheyney lab carrying out aquaponics—using fish to grow plants hydroponically. He compelled the students to enter science as more diversity is needed.

The Lower North Philadelphia CDC is a key partner, providing event coordination and sponsorship, as well as being an organization connector. Their friends at Give and Go Athletics brought a great group of students, who took part in the event and should be commended for taking two hours on a 70° day—after school—to learn more about science! It all seemed well worth it when they got to conduct their own scientific experiments and precipitated DNA from a solution. Eyes widened and smiled through masks. In those few moments you could see in each face that the magic of science homed in and made its first introduction.

VAUX Big Picture High School - Wistar Education Event

Women & Science: Pain, Itch, and Inflammation

Dr. Diana Bautista has dedicated her professional life to the science of literal human connection: our sense of touch.

A Howard Hughes Medical Investigator and professor of cell and developmental biology at University of California, Berkeley, Bautista runs a lab that conducts basic scientific research on touch, particularly itch, pain, and inflammatory diseases.

“Among the five senses, we really know the least about our sense of touch,” Bautista said. “This is surprising given how important touch is in our everyday lives.”

She points to pain as an example of why we need touch to stay healthy and safe. Acute pain, the feeling you get when you touch a hot frying pan, acts as a warning—it triggers a reflex to pull your hand back and prevent tissue damage. Likewise, inflammatory pain from a sunburn will prompt protective behaviors, like covering up before you go back outside, and learning behaviors, like proactively wearing sunscreen.

Chronic pain, however, serves no purpose. It’s like a siren that keeps ringing long after the fire has been put out. It’s a serious problem, afflicting more than 10 million Americans every year. “Which is why we’re working to understand the mechanisms underpinning touch and pain,” said Bautista. She and her colleagues are trying to determine why some people’s pain goes away when they recover from injury or disease, while other people suffer from chronic pain for the rest of their lives.

Bautista’s lab focuses primarily on the first step of feeling physical touch, which is called transduction. In this step, sensory neurons convert a physical stimulus, like the pressure of a handshake or the prick of a pin, into the electrical signals the nervous system uses to communicate. By identifying how these signals are triggered, Bautista hopes to identify new therapeutic targets for mediating pain.

“Our challenge is to discover new genes that underlie the persistence of chronic pain so we can develop new therapies that target pain at its source.” she said.

One gene her lab is researching is TRPM8, which is responsible for sensing cold and menthol. To verify this gene’s function, the scientists set up a mouse experiment. They created a small two-room chamber with an open doorway between the rooms. One room had a comfortably heated floor plate, and the other room had a very cold floorplate. When a regular mouse was put in the chamber, it avoided the cold side. However, when a mouse lacking the TRPM8 gene was placed inside, it traveled between the two chambers indiscriminately, demonstrating no sensitivity to the cold.

The discovery of this gene’s role in cold perception could help lead to treatment for patients suffering from cold allodynia (oversensitivity to cold), chemotherapy-induced neuropathy, and even certain types of migraines.

Another gene Bautista’s lab is studying is S1PR3. Rather than cold, this gene regulates sensitivity to mechanical pain. To test this, the researchers poked mice’s paws with a pin. Normal mice responded to this sensation 100% of the time, whereas mice lacking S1PR3 responded only 40% of the time. This finding is important because the gene is also expressed in human skin, as well as in a variety of other species.

Finally, Bautista’s lab is studying chronic itch, a condition that will affect one in ten people at some point in their lifetime. Like pain, acute itch is protective; it helps to ward off burrowing insects that might carry disease. However, chronic itch can be debilitating.

Historically, chronic itch has been associated with diseases of the integumentary (skin) and immune systems. However, Bautista’s lab has found that the nervous system interacts with the immune system in ways that can trigger inflammation from the skin all the way to the spinal cord. These interactions, which occur early in the sensation of itch, play a significant role in later chronic states of itch and can even go so far as to affect the onset of asthma.

“We’re really excited about this research,” said Bautista. “Very basic science can lead to the discovery of novel therapeutics.”

Wistar Scientists Identify Therapeutic Target for Metastatic Cancers

Damaged “ghost” mitochondria are found to drive tumor progression.

Metastasis, or the spread of cancer from one place in the body to another, is responsible for more than 90% of all cancer deaths. Therefore, determining how and why this happens is an important part of cancer research. A new collaborative study led by scientists at The Wistar Institute identified one such mechanism thanks to “ghost” mitochondria.

Because they are the “powerhouse” of the cell, mitochondria (a specific organelle inside human cells) are crucial for cell survival, including tumor cells. However, recent research has shown that mitochondria in many human tumors lack an important protein called Mic60. Normally missing a crucial protein is a recipe for disaster, yet these mitochondria and their cells survive.

To determine how this is possible and how it affects tumor cell behavior, Dario C. Altieri, M.D., Wistar president and CEO, director of The Wistar Institute Cancer Center, and the Robert & Penny Fox Distinguished Professor, led a team of researchers in reproducing these types of low-Mic60 tumor cells in mice to enable closer examination. In doing so, they found two things. First, in cells where Mic60 was depleted, all of the mitochondria’s structures and functions were damaged or inhibited.

“They really didn’t produce any energy, which is what mitochondria do,” said Altieri. “That was the idea of calling them ‘ghosts’—because in essence the mitochondria were still there, but they didn’t do anything, or anything good, at least.”

Second, the scientists found that while inferior organelles are usually removed from healthy cells via a quality control process, the ghost mitochondria were not removed from tumor cells. Not only were they not removed, but they helped the cell metastasize.

Given these findings, the scientists speculate that the low-Mic60 tumor cells activate two pathways to stay alive: Akt (related to survival) and GCN2 (related to stress response). Drugs interfering with these pathways could, therefore, help to stop metastasis and kill the cancer.

“The idea would be to eliminate the adaptive responses that these Mic60-low tumors mount to remain alive and viable through a combination targeting of Akt and GCN2,” said Altieri.

Wistar Study Opens the Door to Faster, Cheaper HIV Vaccine Research

For the first time, scientists have developed an DNA-encoded immunogen that produces Tier-2 antibodies—the kind that matter for combatting HIV

Nearly four decades after its discovery, HIV has killed 36.3 million people, with no vaccine in sight. Part of the reason vaccine development has been slow is because trialing candidate vaccines that produce Tier-2 neutralizing antibodies—the kind that matter for combatting HIV—has always required long and expensive experiments in large animal models like rabbits and macaque monkeys.

An effective HIV vaccine needs to produce antibodies that protect against the most common variants of HIV, which are categorized as “Tier 2” viruses based on how quickly and easily they can be neutralized by antibodies (more quickly/easily than Tier 3, less than Tier 1).

A new study by scientists at The Wistar Institute shows a quicker, less expensive path to developing this tier of antibodies. For the first time, these scientists have demonstrated a method for eliciting Tier-2 neutralizing antibodies in mice.

“Mice are the workhorse of vaccine design and development because you can iterate lots of concepts in that model due to cost and time constraints,” said Daniel Kulp, Ph.D., associate professor in the Vaccine & Immunotherapy Center at The Wistar Institute.

The scientists developed an immunogen—a substance that causes an immune response—called a native-like trimer, which they administered to mice. Importantly, they encoded the immunogen in DNA, which turns the host bodies (in this case the mice) into “antigen factories” instead of requiring what would otherwise be a complex and expensive vaccine manufacturing process.

They then compared the results from the mice who received the DNA-encoded native-like trimer to results from mice who received a standard protein immunization. Only those mice that received the DNA-encoded native-like trimer developed Tier-2 neutralizing antibodies.

From there, they were able to isolate and examine the atomic structure of one of the antibodies that their immunogen had produced. “The structure gives us incredible insight into how this antibody is able to neutralize the virus,” said Kulp.

“Our data demonstrates the value of this approach as a tool to create surgically tailored immunity against a difficult pathogen’s vulnerable sites, in this case for HIV,” said coauthor David B. Weiner, Ph.D., executive vice president and director of the Vaccine & Immunotherapy Center and the W.W. Smith Charitable Trust Professor in Cancer Research at The Wistar Institute.

Wistar Scientists Move HIV Vaccine Research Forward by Developing an Immunogen that Produces Tier-2 Antibodies—the Kind That Matter for Combatting HIV

PHILADELPHIA — (Feb. 4, 2022) — Nearly four decades after its discovery, HIV has killed 36.3 million people, with no vaccine in sight. However, a new study by researchers at The Wistar Institute, an international biomedical research leader in cancer, immunology, infectious disease, and vaccine development, takes a promising step in the direction of developing an HIV vaccine.

The findings, published in Nature Communications, demonstrate the promise of using a unique native-like trimer to develop Tier-2 neutralizing antibodies—the kind that matter for combatting HIV—in mice for the first time.

Previously, eliciting these types of antibodies using candidate vaccines required long and expensive experiments in large animal models creating a significant bottleneck on HIV-1 vaccine development. “With our new finding, we have opened the door to rapid, iterative vaccinology in a model that can produce Tier-2 neutralizing antibodies, enabling development of more advanced HIV vaccine concepts,” said Daniel Kulp, Ph.D., associate professor in the Vaccine & Immunotherapy Center at The Wistar Institute and corresponding author on the paper.

The researchers encoded the native-like trimer into DNA for delivery into the mice. This has the practical advantage of turning the host bodies into “antigen factories” instead of requiring what would otherwise be a complex vaccine manufacturing process. The researchers then compared the results from the mice who received the DNA-encoded native-like trimer to results from mice who received a standard protein immunization. Only those mice that received the DNA-encoded native-like trimer developed Tier-2 neutralizing antibodies.

“We were able to generate strong immune responses with both platforms, but the DNA platform uniquely drove this neutralizing response,” said Kulp.

Once they’d verified their immunization regime was producing Tier-2 antibodies, Kulp and his colleagues isolated monoclonal antibodies from the mice and used cryo-electron microscopy to determine the atomic structure of one Tier-2 neutralizing monoclonal antibody. They found that the antibody binds to an epitope (a segment of a protein that sticks out of the antigen, which prompts an immune response) called C3V5. In the gold standard HIV vaccine model (non-human primates), prior research has shown that antibodies binding to C3V5 protect animals from a SHIV infection, which is a close relative of HIV that infects non-human primates.

“The structure gives us incredible insight into how this antibody is able to neutralize the virus,” said Kulp. “For the first time, we can strategize about how to design new vaccines that can generate broadly neutralizing antibody responses to the C3V5 epitope.”

Coauthor David B. Weiner, Ph.D., executive vice president and director of the Vaccine & Immunotherapy Center and the W.W. Smith Charitable Trust Professor in Cancer Research at The Wistar Institute, emphasized the utility of their findings.

“What we’ve done is enable direct in vivo self-assembly of structurally designed immunogens, which are engineered and delivered using nucleic acid technology, inside the vaccinated animal. Our data demonstrating induction of autologous Tier 2 neutralization illustrate the value of this approach as a tool to create surgically tailored immunity against a difficult pathogen’s vulnerable sites, in this case for HIV.”

Co-authors: Ziyang Xu, Susanne Walker, Neethu Chokkalingam, Mansi Purwar, Edgar Tello-Ruiz, Yuanhan Wu, Sonali Majumdar, Kylie M. Konrath, Abhijeet Kulkarni, Nicholas J. Tursi, Faraz I. Zaidi, Emma L. Reuschel, Ishaan Patel, April Obeirne, David B. Weiner, and Daniel W. Kulp from The Wistar Institute; Megan C. Wise, Katherine Schultheis, Lauren Gites, Trevor Smith, Janess Mendoza, Kate E. Broderick, and Laurent Humeau from Inovio Pharmaceuticals; Alan Moore, Jianqiu Du, and Jesper Pallesen from Indiana University.

Work supported by: National Health Institutes (NIH) IPCAVD Grant U19 Al109646-04; W. W. Smith Charitable Trust; and Wistar Monica H.M. Shander Memorial Fellowship.

Publication information: Induction of Tier-2 Neutralizing Antibodies in Mice with a DNA-encoded HIV Envelope Native Like Trimer, Nature Communications, 2022. Online publication.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

Wistar Scientists Behind the Next Wave of COVID-19 Vaccines

Current COVID-19 vaccines were created in record time, but scientists are working to make better, longer lasting vaccines that could be used around the world.

The first generation of COVID-19 vaccines have been highly effective, but also have limitations: their efficacy can wane without a booster shot, and they may be less effective against some variants. Now scientists at The Wistar Institute have developed a more targeted vaccine that, in animal studies, shows stronger, broader, and more durable protection in a single, lower dose.

“This is among the first second-generation vaccines that will have more advanced features and broader protection,” said Daniel Kulp, Ph.D., associate professor in the Vaccine & Immunotherapy Center and corresponding author of the study.

The vaccine combines three technologies — immune focusing, self-assembling nanoparticles, and DNA delivery — into a single platform for the first time.

Immune focusing means that researchers engineered an immunogen that targets specific areas of COVID’s famous “spike” protein to generate protective antibodies. Instead of replicating the whole structure, this immunogen blocks specific sites that produce non-neutralizing antibodies. This stimulates higher production of neutralizing antibodies — the kind of antibodies that help the immune system fight the virus.

Having higher levels of these important antibodies can reduce the chance that the vaccine’s effectiveness will wane over time.

Studies in mice found that 100% of animals who received a single dose of the new vaccine were protected from death after virus challenge, whereas only 20% of animals receiving the first-generation vaccine were protected.

Nanovaccines consist of extremely small (nano) particles—similar in size to bacteria and viruses—used to display multiple copies of an antigen and able to elicit strong immune responses. The new vaccine also uses DNA to instruct cells to make these vaccines. Kulp noted that DNA vaccines can be stored at room temperature, making it potentially easier to transport to remote or developing locations than existing approved vaccines (such as mRNA vaccines), which require specialized cold storage. DNA vaccines historically also have an excellent safety profile, with a very low chance of eliciting severe adverse effects amongst clinical trial participants.

“Current vaccine effects on reducing transmission of SARS-CoV-2 variants of concern including Delta and Omicron could be improved for their breadth of protection as well as their immune potency,” said co-author David B. Weiner, Ph.D., executive vice president, director of the Vaccine & Immunotherapy Center and the W.W. Smith Charitable Trust Professor in Cancer Research, at The Wistar Institute.

The scientists are seeking funding and partnership to begin human trials of the new vaccine.

Dr. Kulp’s research was made possible through the generous support of Wistar donors who contributed to this project through the Wistar Coronavirus Discovery Fund.